Shikonin alleviates bone cancer pain through suppression of spinal IGF2-associated p38 MAPK signaling
Background Bone cancer pain (BCP) is a debilitating complication of advanced cancer that substantially impairs physical function and emotional wellbeing. Current pharmacological treatments often provide incomplete analgesia and may be limited by adverse effects. Shikonin, a bioactive naphthoquinone derived from Lithospermum erythrorhizon, exhibits analgesic and anti inflammatory activities, but…
Bone cancer pain (BCP) poses significant challenges for patients, affecting their ability to function physically and emotionally. Current treatments often fall short in providing sufficient relief, leading to potential side effects. Shikonin, a bioactive compound found in Lithospermum erythrorhizon, has shown promise in alleviating BCP pain, but its mechanism remains unclear.
To investigate, researchers established a rat model of BCP via intratibial inoculation of labeled MADB106 cells. The study examined Shikonin's analgesic and behavioral effects using various tests, including mechanical and thermal nociceptive assessments, gait analysis, open field tests, elevated plus maze, light/dark box, and rotarod performance. They also analyzed spinal tissue for tumor growth, bone pathology, and biomarkers.
Transcriptomic sequencing of the spinal dorsal horn revealed IGF2 as a candidate gene responsive to Shikonin treatment. Spinal IGF2 and p38 phosphorylation levels were elevated during BCP development. Intrathecal Shikonin demonstrated dose-dependent antinociceptive effects, reducing pain and improving mobility without affecting rotarod performance. Shikonin also alleviated pain-related anxiety-like behaviors.
Further analysis indicated that Shikonin reduced IGF2 expression and p38 phosphorylation in the spinal dorsal horn, leading to decreased proinflammatory cytokines IL-6, IL-1β, and TNF-α. Knockdown of IGF2 reproduced Shikonin's analgesic and behavioral effects while p38 inhibition achieved similar behavioral benefits without a significant change in IGF2 expression. However, combining Shikonin with either IGF2 knockdown or p38 inhibition yielded no additional behavioral advantages.
The study concludes that intrathecal Shikonin effectively alleviates nociceptive hypersensitivity, functional impairment, and pain-related anxiety in rats with induced BCP. The observed phenocopying and non-additive effects of IGF2 knockdown and p38 inhibition further suggest the involvement of an IGF2-associated p38 MAPK signaling axis in Shikonin's analgesic actions.
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